The goal of this research is to develop, integrate, and evaluate novel informatics techniques to optimize the mammographic diagnosis of breast cancer in aging women. Women over age 65 who develop breast cancers have greater death rates and poorer outcomes. These women also bear the heaviest burden of overdiagnosis a phenomenon in which screening identifies cancer which may not go on to cause symptoms or death. These sobering statistics are made more urgent by the realization that the number of women > 65 is projected to more than double (from 20-40 million) between 2000 and 2050. In this research program, we propose to develop tools that will improve the early diagnosis of invasive breast cancer, minimize unnecessary invasive procedures (decrease false positives) and concomitantly address overdiagnosis. Specifically we aim to 1) develop a probabilistic computer model trained by a novel machine learning algorithm, Prediction using Logical Uplift Modeling (PLUM), that tailors breast cancer risk estimations to aging women; 2) use a decision analytic model to determine the optimal breast biopsy threshold using an important pathologic prognostic indicator, cytologic grade in the context of age, and 3) use comparative effectiveness analysis to determine how these personalized risk prediction strategies and optimal thresholds for action will improve on current breast cancer screening policies in women > 65. Our multidisciplinary team has a track record (including NIH funding and publications in the medical, engineering, and computer science literature) of innovative research that integrates state-of-the-art informatics algorithms to improve breast cancer diagnosis. Using prior experience and infrastructure, we are building a completely new machine learning algorithm, PLUM, which uses 1) inductive logic programming (ILP) to accurately learn from multi-relational data; 2) uplift modeling that uses age as a partition, and 3) rule incorporation into our probabilistic model for accurate risk prediction. We necessarily use a uniquely rich clinical data, a deep understanding of disease processes, and creative integration of these computational tools. New preliminary data presented in this resubmission foreshadow scientific success and clinical translation. If supported, this project will prove that risk prediction and decision analytic tools can accurately assess breast cancer risk, determine an optimal, personalized biopsy threshold, and provide a superior breast cancer screening policy than is currently employed in the US for women over age 65.